Lenalidomide, chemically (RS)-3-(4-Amino-1-oxo 1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione of formula (I),
is a pharmaceutically active compound used for the treatment of multiple myeloma and Myelodysplastic syndromes
The compound was discovered by Celgene and is disclosed in EP925294. Lenalidomide is the active ingredient in the medicinal product sold under the brand name Revlimid®.
Lenalidomide exhibits polymorphism. WO2005023192 discloses crystalline forms of lenalidomide, its process of preparation, compositions comprising these crystalline forms and its use for treatment of diseases. Polymorph B is the most stable form and is present in the marketed tablets. Compositions comprising both amorphous and crystalline lenalidomide are also disclosed in this application. Other polymorphic forms of lenalidomide are disclosed in WO2011111053. The prior art thus teaches that lenalidomide crystallizes very easily. Moreover, it was experienced in our laboratory that polymorphic transitions of lenalidomide take place rather easily, especially in drug product.
Lenalidomide is slightly soluble in water. Conventional approaches to increase solubility consist on micronizing the API. Nevertheless, it was experienced in our laboratory that micronization of lenalidomide gave partially amorphous solid, which readily converts to other crystalline forms. It is known that generally the solubility of amorphous forms is higher compared to the solubility of crystalline forms. In view of this, it would be desirable to produce stable amorphous lenalidomide and to find a robust process for making such a stable amorphous lenalidomide.
WO2010054833 and WO 2009114601 disclose solid dispersions containing amorphous lenalidomide.
Although many drugs can be solubilized by cyclodextrin it is not apparent that the inclusion complex obtained is completely amorphous.
CN103705485 discloses the use of beta cyclodextrines as solubilising agent in lenalidomide formulations in a ratio of 1:8. It was experienced in our laboratory that in this ratio the inclusion complex obtained is partially amorphous and therefore not stable.
Thus in view of the prior art cited above, there is still a need for alternative pharmaceutical compositions comprising lenalidomide, or a pharmaceutically acceptable salt thereof, which are stable and suitable for use on a commercial scale.